Chronic pain represents a major health and economic problem throughout the world. Despite major advances in understanding the physiological and pathological basis of pain, and ideal analgesic is yet to be discovered. Among analgesic drugs, the opioid class of compounds still remain the effective treatment agents for severe and chronic pain. For instance, see Parrot, Using Opioid Analgesic to Manage Chronic Noncancer Pain in Primary Care, J. Am. Board Fam. Pract. 1999, 12, 293-306 and Cherny, New Strategies in Opioid Therapy for Cancer Pain, J. Oncol. Manage 2000, 9, 8-15.
The opioid drugs produce their biological effects through their interaction with opioid receptors, which belong to the family of seven transmembrane G-protein coupled receptors. The existence of three opioid receptor types μ, δ and κ has been clearly established and is confirmed by cloning of these three receptors from mouse, rat, and human cDNAs. Along these lines, see Dhawan et al. International Union of Pharmacology. XII. Classification of Opioid Receptors, Pharmacol. Rev. 1996, 48, 567-592; and Aldrich, Analgesics, In Burger's Medicinal Chemisty and Drug Discovery, 5th ed.; Wolff, M. E., Ed.; John Wiley & Sons: New York, 1996; Vol. 3. Therapeutic Agents; pp 321-441.
All three opioid receptor types are located in the human central nervous system and each has a role in the mediation of pain. Morphine and related opioids currently prescribed as potent analgesics for the treatment of pain produce their analgesic activity primarily through their agonist action at the μ opioid receptors. The general administration of these medications is limited by significant side effects such as respiratory depression, muscle rigidity, emesis, constipation, tolerance, and physical dependence. For example, see Duthie, Adverse Effects of Opioid Analgesic Drugs, Br. J. Anaesth. 1987, 59, 61-77 and van Ree et al., Opioids, Reward and Addiction: An Encounter of Biology, Psychology, and Medicine. Pharmacol. Rev. 1999, 51, 341-396.
A large body of evidence indicates the existence of physical or functional interactions between μ and δ receptors. Ligands with agonist or antagonist action at the δ receptor, for example, have been shown to modulate the analgesic and adverse effects of μ agonists. See, for instance, Traynor et al., δ-Opioid Receptor Subtypes and Cross-talk with μ-receptors. Trends Pharmacol. Sci. 1993, 14, 84-86; Rothman et al., Allosteric Coupling Among Opioid Receptors: Evidence for an Opioid Receptor Complex, In Handbook of Experimental Pharmacology, Volume 104, Opioid I; Hertz et al., Eds; Springer-Verlag: Berlin, 1993; pp 217-237; Jordan et al., G-Protein-Coupled Receptor Heterodimerization Modulates Receptor Function. Nature 1999, 399, 697-700; George et al., Oligomerization of μ- and δ-Opioid Receptors, J. Biol. Chem. 2000, 275, 26128-26135; Levac et al., Oligomerization of Opioid Receptors: Generation of Novel Signaling Units, Curr. Opin. Pharmacol., 2002, 2, 76-81.
On the other hand, agonist action at the δ receptors potentiate μ mediated analgesic effects, antagonist action at the δ receptor suppresses the tolerance, physical dependence, and related side effects of μ agonists without affecting their analgesic activity. In a study using the nonpeptide ligand naltrindole, Abdelhamid et al. demonstrated that the δ receptor antagonist greatly reduced the development of morphine tolerance and dependence in mice in both the acute and chronic models without affecting the analgesic actions of morphine. See Abdelhamid et al., Selective Blockage of Delta Opioid Receptors Prevents the Development of Morphine Tolerance and Dependence in Mice. J. Pharmacol. Exp. Ther. 1991, 258, 299-303.
Fundytus et al., reported that continuous infusion of the δ selective antagonist TIPP[Ψ] by the intracerbroventricular (icv) route in parallel with continuous administration of morphine by the subcutaneous route to rats attenuated the development of morphine tolerance and dependence to a large extent. See Fundytus, et al., Attenuation of Morphine Tolerance and Dependence with the Highly Selective δ-Opioid Receptor Antagonist TIPP[ψ], Eur. J. Pharmacol. 1995, 286, 105-108.
Schiller et al., found that the peptide ligand DIPP-NH2[Ψ] displayed mixed μ agonist/δ antagonist properties in vitro and that the compound given icv produced analgesic effect with no physical dependence and less tolerance than morphine in rats. See Schiller et al., Four different types of Opioid Peptides with mixed μ Agonist/δ Antagonist Properties Analgesia 1995, 1, 703-706; and Schiller et al., The Opioid μ Agonist/δ Antagonist DIPP-NH2[ψ] Produces a Potent Analgesic Effect, No Physical Dependence, and Less Tolerance than Morphine in Rats, J. Med. Chem. 1999, 42, 3520-3526.
Studies with antisense oligonucleotides of δ receptor have demonstrated that reduction of δ receptor expression diminishes the development and/or expression of morphine dependence without compromising antinociception produced by μ agonists. See Suzuki et al., Antisense Oligodeoxynucleotide to δ Opioid Receptors Attenuates Morphine Dependence in Mice, Life Sci. 1997, 61, PL 165-170; and Sanchez-Blazquez et al., Antisense Oligodeoxynucleotides to Opioid Mu and Delta Receptors Reduced Morphine Dependence in Mice: Role of Delta-2 Opioid Receptors, J. Pharmacol. Exp. Ther. 1997, 280, 1423-1431. Furthermore, genetic deletion studies using δ receptor knockout mice have shown that these mutant mice retain supraspinal analgesia and do not develop analgesic tolerance to morphine. Zhu et al., Retention of Supraspinal Delta-like Analgesia and Loss of Morphine Tolerance in δ Opioid Receptor Knockout Mice, Neuron, 1999, 24, 243-252.
These observations suggest that the development of opioid ligands, especially nonpeptide ligands possessing mixed μ agonist/δ antagonist activity may provide a novel approach for the development of analgesic agents with low propensity to produce tolerance, physical dependence, and other side effects.
In studies on naltrexone-derived heterocycle annulated morphinan ligands, it was found that the pyridomorphinan 2a (chart 1) displayed high affinity binding at the opioid receptors and that the binding affinity and antagonist potency of the pyridomorphinans at the δ receptors are modulated by the substituents placed at the 5′-position on the pyridine moiety. For example, the introduction of aromatic groups such as a phenyl group (2b) (chart 1) or a 1-pyrrolyl group at this position gave ligands with high binding affinity and improved δ antagonist potency as determined in bioassays using mouse vas deferens smooth muscle preparations. See Ananthan et al. (I), Synthesis, Opioid Receptor Binding, and Biological Activities of Naltrexone-Derived Pyrido- and Pyrimidomorphinans, J. Med. Chem. 1999, 42, 3527-3538; and Ananthan et al. (II), Synthesis, Opioid Receptor Binding, and Functional Activity of 5′-Substituted 17-Cyclopropylmethylpyrido[2′,3′:6,7]morphinans. Bioorg. Med. Chem. Lett. 2003, 13, 529-532.
Interestingly, among phenyl ring substituted analogues of 2b (chart 1), the p-chlorophenyl compound (2c) (chart 1) displayed a mixed μ agonist/δ antagonist profile of activity in the smooth muscle assays in vitro. See Ananthan et al. (I), supra. In analgesic activity evaluations, this compound displayed partial agonist activity in the tail-flick assay and a full agonist activity in the acetic acid writhing assay after icv or ip administration in mice, and it did not produce tolerance to antinociceptive effects on repeated ip injections. Studies in mice with selective antagonists, characterized this compound as a partial μ agonist/δ antagonist. See Wells et al., In Vivo Pharmacological Characterization of SoRI 9409, a Nonpeptidic Opioid μ-Agonist/δ-Antagonist That Produces Limited Antinociceptive Tolerance and Attenuates Morphine Physical Dependence. J. Pharmacol. Exp. Ther. 2001, 297, 597-605.
Paradoxically, however, in the in vitro biochemical assays using [35S]GTP-γ-S binding, compound 2c(chart 1) failed to display μ agonist activity in guinea pig caudate membranes as well as in cloned cells expressing human μ receptors. See Xu et al., SoRI-9409, a Non-peptide Opioid μ Receptor Agonist/δ Receptor Antagonist, Fails to Stimulate [35S]-GTP-γ-S Binding at Cloned Opioid Receptors. Brain Res. Bull. 2001, 55, 507-511.